microrna networks regulate the differentiation, expansion ...microrna networks regulate the...
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MicroRNA networks regulate the differentiation, expansion and
suppression function of myeloid-derived suppressor cells in tumor
microenvironment
Yanping Sua, Ye Qiub, Zhidong Qiuc, Peng Qu*d
a Department of Histology and embryology, Shangdong First Medical
University, Taian, Shangdong, China. b National Engineering Lab for Druggable
gene and protein screening, Northeast Normal University, Changchun, Jilin,
China. c Department of pharmacy, Changchun University of Chinese Medicine,
Changchun, Jilin, China. d National Cancer Institute, National Institutes of
Health, Frederick, MD, USA
*Address correspondence to:
Peng Qu, Ph.D.
National Cancer Institute
1050 Boyles St., Bldg 560, Rm 12-34
Frederick, MD 21702, USA
Phone: 301-846-5692
E-mail: [email protected]
Key words: MicroRNA, Myeloid-derived suppressor cells, Tumor
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Abstract
Myeloid-derived suppressor cells (MDSCs), one heterogeneous population of
immature myeloid cells, have suppressive function on immune response during
tumor, inflammation, infection and autoimmune diseases. The molecular
mechanism underlying expansion and function of MDSCs is becoming
appreciated to manipulate immune response in the diseases. MicroRNA
(miRNAs) as one short noncoding RNAs, are involved in regulating cell
proliferation, differentiation and maturation. However, it needs to be further
studied how miRNAs mediate the development and function of MDSC in
association with cancer and other diseases. In the review, we report and
discuss recent studies that miRNAs networks regulate the differentiation,
expansion and suppression function of MDSCs in tumor microenvironment or
other diseases through different signaling pathways. Those studies may
provide one novel potential approach for tumor immunotherapy.
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Introduction
Myeloid-derived suppressor cells (MDSCs) are the progenitors of myeloid cells
with suppressive function on immune response in tumor microenvironment
(TME). In tumor bearing-mice, MDSCs are generally characterized as GR-
1+CD11b+ cells, which are further divided as two subtypes: CD11b+Ly6G-
Ly6Chigh monocytic MDSCs and CD11b+Ly6G+ Ly6Clow granulocytic
MDSCs[1, 2]. They utilize different suppressive mechanisms to inhibit the
antitumor immune response. Monocytic MDSCs regulates immune suppression
through the production of NO and arginase[3]. In contrast, the inhibition of
granulocytic MDSCs is regulated via ROS and H2O2 [4]. In patients with cancer,
there are different types of MDSCs. In general, MDSCs are characterized as
CD33+CD15+CD14-HLA-DRlow populations [5]. Many factors, such as
cytokines, growth factors and microbial products released in tumor
microenvironments have been shown to be involved in the induction and
expansion of MDSCs with suppressive activity[6, 7]. Most of these mediators
activate signaling pathways in tumor MDSCs that involve NF-κB and STATs [1,
8, 9] . Some novel regulatory mechanisms for the differentiation, expansion and
suppression of tumor MDSCs were described recently. There is emerging
evidence that microRNAs (miRNAs) cooperate transcriptional factors to
become complex regulatory networks which mediate tumor MDSCs[10, 11].
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miRNAs are the abundant small, single-stranded, non-coding RNA of about 22
nucleotides. miRNAs base-paired with the complementary sequence within
target mRNAs to mediate post-transcriptional gene repression or target mRNA
degradation [12]. The stability of the miRNA–mRNA interaction is critical for
repressing the potential target [13]. Each mRNA could be targeted by different
miRNAs and a single miRNA may target different mRNAs [14, 15]. Gene
expression silencing by means of miRNAs and changes in the miRNA
expression level regulate various biological processes, including the
differentiation, maturation, function of immune cells and maintenance of
immune homeostasis [16-19]. MDSCs , an immune-suppressive cell, plays an
important role in a wide range of human diseases including cancer, chronic
inflammatory and autoimmune diseases. Therefore, both abnormal expression
and function of miRNAs in MDSCs were investigated, so that Novel miRNAs
regulatory mechanisms on MDSCs were displayed.
MicroRNAs regulate the differentiation and activation of tumor MDSCs
1. miRNAs up-regulation on tumor MDSCs
Recent reports demonstrated that miR-494 expression in tumor MDSCs was
dramatically induced by tumor-derived factors, such as TGF-β1 to regulate the
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accumulation and activity of MDSCs by targeting of phosphatase and tensin
homolog (PTEN) and activation of the Akt pathway [20]. miR-10a activate
AMPK signaling to promote expansion and activation of MDSCs in breast
cancer cells with chemotherapy-induced immune resistance [21]. miR-6991-
3p could directly target the immune checkpoint gene LGALS9 and MiR-6991-
3p mimic transfection suppressed expansion and promoted apoptosis of
MDSCs through suppressing LGALS9-mediated activation of STAT3 [22]. In B
lymphoma -bearing mice, miR-30a expression was increased in both G-MDSCs
and M-MDSCs. After the transfection of miR-30a mimics, the differentiation and
suppressive abilities of MDSCs were increased via up-regulation of arginase-
1. miR-30a also down-regulated suppressor of cytokine signaling 3 (SOCS3)
mRNA to activate STAT3 signaling to promote MDSC differentiation and
suppressive activities, indicating that same individual microRNA can regulate
differentiation and activity of MDSCs through difference pathways [23, 24]
(Figure1). The inhibition of miR-9 promoted the differentiation of MDSCs with
significantly reduced immunosuppressive function via by targeting the runt-
related transcription factor 1 (Runx1), an essential transcription factor in
regulating MDSC differentiation and function [25] (Figure2).
2. Inhibitory roles of miRNAs on tumor MDSCs.
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miRNAs also negatively mediate the differentiation and activity of tumor
MDSCs. The overexpression of miR-17 family members such as miR-17-5p,
miR-20a and miR-106a in human progenitor cells represses AML1 by binding
to its promoter, which results in the down-regulation of M-CSFR, thus limiting
MDSC differentiation [26] (Figure2). In LLC and ovarian carcinoma models,
miR-223 suppresses differentiation and accumulation of MDSCs by targeting
molecule myocyte enhancer factor 2C (MEF2C) [27]. miR-142-3p can prevent
MDSC differentiation during tumor-induced myelopoiesis by modulating STAT3
and C/EBPβ signal pathway, indicating that the potential therapeutic application
for miR-142-3p oligonucleotide as adjuvant tool for adoptive T cell therapy of
cancer [28] (Figure1).
3. miRNAs from tumor-derived extracellular vesicles
extracellular vesicles (EVs) were involved in miRNAs regulation on MDSCs.
Cancer cells secreted EVs, which were involved in the intercellular transfer of
proteins, lipids, and genetic material (such as miRNAs). Those tumor-
associated EVs represented an ideal candidate due to their ability to recirculate
in body fluids during the process of MDSC generation from bone marrow in
tumor microenvironment[29-31]. In melanoma patients, some miRNAs (such as
miR-99b, miR-100, miR-125a/-125b, miR-146a/-146b, miR-155, let-7e), which
are highly detected in plasma as associated with EVs, mediate the generation
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and functional features of tumor M-MDSCs [8, 32, 33]. In Acute myeloid
leukemia (AML), miR-34a promotes the expansion of MDSCs as the regulatory
mechanism by which MUC1 drives c-myc expression in Acute AML cells and
tumor-derived EVs [30]. In addition, miR-34a also inhibited the apoptosis of
MDSCs via targeting N-myc [34] or p2rx7/Tia1 [35] (Figure2). Those data
suggested that miR-34a upregulated the generation and accumulation of tumor
MDSC through different pathways as many other miRNAs.
4. miRNAs from tumor-derived exosomes
Exosomes derived from tumor (such as gliomas) are also involved in MDSC
differentiation. In glioma-bearing mice, glioma-derived exosomes (GDEs)
facilitate the expansion and function of MDSCs. Hypoxia promoted the
upregulation of miR-10a and miR-21 expression in GDEs to induce MDSC
activation by targeting the IκBα/NF-κB and PTEN/PI3K/AKT pathways. The
reduced numbers of MDSCs were observed in the spleens of mice bearing miR-
10a or miR-21 knockout glioma cells, compared with those in bearing glioma
cells [36]. Those GDEs also regulated the expansion of MDSCs through
miRNA-29a/Hbp1 and miRNA-92a/Prkar1a pathways [37], indicating that
GDEs can regulate MDSC expansion through difference miRNAs (Table1).
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miRNAs mediate the function of MDSCs in tumor microenvironment
1. miRNAs regulate MDSCs through Stat3 pathway
We ever discussed the findings about the relationship between miRNAs and
JAK/STAT3 in cancer [2, 8]. Recently, there were more emerging data about
negative and positive regulation of miRNAs networks and JAK/STAT3 signaling
pathways via direct and indirect regulatory mechanisms in tumor
microenvironment (Figure 1). STAT3, as an important transcript factor, is also
required for the suppressive function of tumor MDSCs [2, 38-40]. Therefore, we
focus on the regulation of miRNAs on tumor MDSC through JAK/STAT3 further.
Recent data demonstrated that four members of miR-17 family (including miR-
17, miR-20a, miR-93, miR-106a) played inhibitory roles in the function of tumor
MDSCs. In tumor microenvironment, tumor-associated factors downregulate
the expression of miR-17-5p and miR-20a and promote the Stat3-associated
suppressive function of MDSCs [41]. Thus, miR-17-5p and miR-20a can
potentially be used as targets in immunotherapy strategies to inhibit the function
of MDSCs via reducing STAT3 expression[42].
The enhanced expression of miR-142-3p reduced the immunosuppressive
activity of tumor BM-MDSCs, restoring CD8+ T cell proliferation through
inhibiting C/EBPβ/STAT3 pathway [28]. miR223 and Let7e also downregulate
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the suppressive function of MDSCs through inhibiting the activation of STAT3
in Gliomas [41]. The expression of PD-L1 on tumor MDSC, which are closely
related to the suppressive function of MDSCs, was regulated by the miR-
93/106b miRNA cluster of miR-17 family through stat3 pathway. Those PD-L1
expression levels on MDSCs can be reduced significantly after treatment of
miR-93 mimics [43, 44]. Therefore, those miRNAs above regulate tumor
MDSCs plasticity through inhibiting STAT3 pathways (Figure1).
The regulatory roles of miRNAs on tumor MDSCs are positively involved in
STAT3 pathway. miR-200c promotes suppressive potential of tumor MDSCs by
targeting PTEN/friend of Gata 2 (FOG2), which can lead to STAT3 and
PI3K/Akt activation [45]. miR-155 and miR-21 showed a synergistic effect on
MDSC induction via targeting SHIP-1 and PTEN respectively, leading to Stat3
activation [46]. In a line with this finding above, MDSCs was shown to require
miR-155 to facilitate tumor growth [47]. However, recent study revealed the loss
of miR-155 in MDSCs enhanced its recruitment and function in solid tumor,
which is not consistent with the results above [11, 48].
2. miRNAs regulate MDSCs through PD-L1/PD-1 pathway
The immunotherapy of checkpoints PD-L1/PD-1 on tumor have been broadly
applied and those Checkpoints were also associated with the tumor MDSCs [1,
8]. But the interaction between miRNAs and checkpoints PD-L1/PD-1 on tumor
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MDSCs was recently investigated. Some scientists reported that five members
of miR-15 family, which include miR-15a, miR-15b, miR-16, miR-195 and miR-
503, activate T cell response by inhibiting the function of MDSCs and/or Tregs
in the tumor microenvironment through blocking PD-L1/PD-1 signaling pathway
[42, 45, 49, 50], however, miR-424(322), another member of miR-15 family was
inversely correlated with PD-L1 pathways. High levels of miR-424(322) in the
tumor were positively correlated with the function of MDSCs and Tregs [51]
(Figure2). The latest results demonstrated that hypoxic tumor-derived
exosomes (TEXs) enhanced the suppressive roles of MDSCs on γδ T cells
through a miR-21/PTEN/PD-L1 pathway in oral squamous cell carcinoma
(OSCC) [52]. Thus, interaction between miRNAs network and PD-L1/PD-1
regulates the expansion and function of tumor MDSCs, providing one novel
therapy method for inhibiting MDSC-associated tumor metastasis (Table 2).
3. miRNAs regulate MDSCs through other molecular pathways
miRNAs networks regulate the function of MDSCs through other target genes.
Recent studies demonstrated that EL-4 tumor-elicited MDSCs showed
increased expression of miR-690 with attenuated C/EBPα expression [50].
Hypoxia-induced miR-210 enhanced the immunosuppressive activity of tumor
MDSCs by increasing arginase activity, nitric oxide production and IL-16 [53].
It was reported that the expansion of tumor MDSCs was regulated by miR-494
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through PTEN/AKT. The downregulation of PTEN by miR-494 enhanced the
activity of AKT to promote the accumulation of MDSCs in tumor tissues [20].
miR-492 also play similar roles in the suppressive function of MDSCs[54]. In
melanoma patients, several miRNAs (including miR-100 family member-miR-
99b/-100 and miR-125 family members-miR-125a/-125b) induced the activity
and accumulation of MDSCs through IL-6 and CCL2, activating JAK/STAT3
pathway further [32] (Figure1).
MicroRNAs regulate the expansion and function of MDSCs in
inflammation, infection and autoimmune diseases
1. Inflammation and infection
MDSCs also play an important role in other pathological conditions, including
inflammation, infection and autoimmune diseases [2, 10, 55]. Thus, we
examined if miRNAs had regulatory roles on MDSCs in those diseases. In
mouse model with chronic asthma, miR-20b Induced the increased numbers of
MDSCs in lung through TGF-β to inhibit airway inflammation[56]. MDSCs
enhance late sepsis development through immunosuppressive function in
mice. miR-375 can regulate the function and miR-21 expression of those
MDSCs through targeting Janus kinase 2 (JAK2) and further impaired STAT3
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in the mice with sepsis [57]. miR-21 and miR-181b couple with NFI-A to
promote immunosuppression of MDSCs for improving late-sepsis survival [58].
The overexpression of some miRNAs is induced by the synergistic effect of
STAT3 and C/EBPβ, which activate miR-21 and miR-181b promoters after
sepsis initiation [59]. The latest results demonstrate that S100A9 stabilizes
those STAT3/C/EBPβ protein complex to promote MDSC expansion and
immunosuppression in late/chronic sepsis by inducing the expression of miR-
21 and miR-181b [60]. In inflammation environment, TNFα-mediated miR-136
also target NFI-A to induce differentiation and activity of MDSCs [61]. MDSCs
and Tregs were developed during chronic hepatitis C virus (HCV) infection.
miR-124 downregulated the expression level of STAT3, as well as TGF-β,
which were overexpressed in MDSCs to reduce the frequencies of MDSCs and
Tregs , thus uncovering a novel mechanism for the expansion of MDSC and
Tregs during HCV infection [62].
2. Autoimmune Disease
Recent studies demonstrated that MDSCs are involved in autoimmune
diseases. In experimental autoimmune encephalomyelitis (EAE), MDSCs can
suppress T cell activities, in which miR-223 downregulate the number and
function of MDSCs via STAT3. In miR-223 knockout mice, MO-MDSCs
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suppressed T cell proliferation in vitro and EAE in vivo more than wild-type MO-
MDSCs[63] (Table 3).
Concluding remarks
MDSCs are one of important immune suppressive cells in tumor
microenvironment and may be next breakthrough target for tumor
immunotherapy [5, 6, 64]. The expansion and function of tumor MDSCs have
been widely investigated, however, the regulatory mechanism of MDSCs need
be further defined[5, 55, 65]. Recently, the novel research field of miRNA
regulation on tumor MDSCs plasticity were opened[32, 66, 67]. The
differentiation and function of MDSCs seems to be regulated by multiple
miRNAs, some of which were classified by us based on their family members,
in order that the scientists may investigate the regulatory roles of other related
members of miRNAs family on tumor MDSCs. However, it remains to be
clarified how those dysregulated miRNAs were combined in vivo to act on
MDSCs on key signaling pathway. In addition, most of research data about
miRNA function on tumor MDSCs were gained from murine studies, even
though there are a few miRNA data from human patients with cancer. The
significant and application of miRNAs for the expansion and function of MDSCs
in patients with cancer need be further investigated. Therefore, the interaction
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of dysregulated miRNAs on MDSCs with transcription factors, cofactors and
chromatin modifiers may target specific miRNA-regulated pathways to provide
novel ways to treat MDSCs in tumor microenvironment.
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Acknowledgements
This work was supported by National Natural Science Foundation of China
(Grant No. 81572868); Natural Science Foundation of Shangdong (Grant No.
ZR2014ZM023). Jilin province science and technology development program
(20160201001YY, 20170520043JH); Foundation of Jilin Educational
Committee (JJKH20170726KJ); Intramural Research Program at the NCI.
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Figure1. The interaction between microRNAs and Stat3 in tumor microenvironment.
MicroRNAs (miRNAs) are emerging as direct or indirect regulators of Janus Kinase (JAK)–
Signal Transducer and Activator of Transcription 3 (STAT3) pathways in the pathogenesis of
cancer. In each process, microRNAs networks play positive (black line) or negative (orange
line) roles. SOCS1: Suppressor Of Cytokine Signaling 1; SOCS3: Suppressor Of Cytokine
Signaling 3; PTEN: Phosphatase and Tensin Homologue; ZEB1: Zinc Finger E-Box Binding
Homeobox 1; EGFR: Epidermal Growth Factor Receptor.
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Figure2. Effect of microRNA networks on MDSCs’ differentiation, expansion,
activation and function in tumor microenvironment.
In tumor microenvironment, MDSCs from Immature myeloid cells are divided as two
subtypes: monocytic MDSCs (M-MDSCs) and Granulocytic MDSCs (G-MDSCs),
which utilize different suppressive mechanism to inhibit the antitumor ability of T
cells. In each process, microRNAs networks play positive (black line) or negative
(orange line) roles.
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Table 1. microRNAs regulation on the differentiation and expansion of tumor
MDSCs
MicroRNAs Target genes References
miR-9 Runx1 [25]
miR-10a AMPK [21]
miR-10a/-21 Rora/NF-κB [36]
miR-17-5p/-20a (miR-17 family) AML1 [26]
miR-106a (miR-17 family) AML1 [26]
miR-30a SOCS3/Stat3 [24]
miR-34a MUC-1 [30]
miR-34a N-myc [34, 35]
miR-92a Prkar1a [37]
miR-125b TNF [8]
miR-146a CSF-1R [33]
miR-142-3p C/EBPβ/Stat3 [28]
miR-155 C/EBPβ [46, 47]
miR-223 MEF2C [27]
miR-494 PTEN [20]
miR-6991-3p Stat3 [22]
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Table 2. microRNAs mediate the function of MDSCs in tumor
microenvironment
MicroRNAs Target genes References
miR-15a (miR-15 family) PD-1/PD-L1 [50]
miR-16/195 (miR-15 family) PD-1/PD-L1 [49]
miR-503 (miR-15 family) PD-1/Stat3 [42]
miR-424(322) (miR-15 family) PD-1/PD-L1 [51]
miR-17-5p/-20a (miR-17 family) Stat3 [42]
miR-93/-106b (miR-17 family) Stat3 [43, 44]
miR-21 Stat3 [46]
miR-21 PTEN/PD-L1 [52]
miR-99b/-100 (miR-100 family) IL-6/CCL2 [32]
miR-125a/-125b (miR-125 family) IL-6/CCL2 [32]
miR-136 NFIA [61]
miR-142-3p C/EBPβ/Stat3 [28]
miR-155 Stat3 [11, 46]
miR-155 MCL-1 [48]
miR-200C PTEN/FOG2 [45]
miR-210 NO production [53]
miR-223 Stat3 [41]
miR-492 PTEN [54]
miR-494 PTEN [20]
miR-690 C/EBPa [50]
Let7e Stat3 [41]
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Table 3. microRNAs regulate the expansion and function of MDSCs in
inflammation, infection and autoimmune diseases
MicroRNAs Diseases/ MDSC plasticity Target genes References
miR-20b Asthma/Expansion TGFβ [56]
miR-21 Sepsis/Expansion NFI-A [58]
miR-124 HCV/Suppressive function Stat3 [62]
miR-136 Inflammation/ differentiation NFI-A [61]
miR-181b Sepsis/ Expansion NFI-A [58]
miR-223 EAE/Suppressive function Stat3 [63]
miR-375 Sepsis/Expansion Jak2-stat3 [57]